A5014617287- Alzheimer's disease research and treatments
- Down syndrome and intellectual disability research
- Neuroscience and Neuropharmacology Research
- Microtubule and mitosis dynamics
- Mitochondrial Function and Pathology
- Cellular transport and secretion
- Cholinesterase and Neurodegenerative Diseases
- Prion Diseases and Protein Misfolding
- Neurogenesis and neuroplasticity mechanisms
- Neuroinflammation and Neurodegeneration Mechanisms
- Trace Elements in Health
- Genetics and Neurodevelopmental Disorders
- HIV Research and Treatment
- Dementia and Cognitive Impairment Research
- Signaling Pathways in Disease
- RNA Interference and Gene Delivery
- Tryptophan and brain disorders
- Ion channel regulation and function
- Autism Spectrum Disorder Research
- S100 Proteins and Annexins
- ATP Synthase and ATPases Research
- Frailty in Older Adults
- Cell death mechanisms and regulation
- Axon Guidance and Neuronal Signaling
- Pluripotent Stem Cells Research
University of California, Irvine
2015-2025
Irvine University
2018
UC Irvine Health
2006-2014
Marche Polytechnic University
2011
Institute of Neurobiology
2006-2009
UConn Health
1998-2003
Boston Children's Hospital
1993-1998
Stanley Foundation
1998
Dana-Farber Cancer Institute
1993-1997
Harvard University
1991-1997
The cellular mechanism underlying the generation of beta-amyloid in Alzheimer disease and its relationship to normal metabolism amyloid precursor protein are unknown. In this report, we show that 3- 4-kDa peptides derived from normally secreted. Epitope mapping radiolabel sequence analysis suggest peptide is closely related full-length 3-kDa species a heterogeneous set truncated at N terminus. secreted parallel with protein. Inhibitors Golgi processing inhibit secretion peptides, whereas...
Deposition of the beta-amyloid protein in senile plaques is a pathologic hallmark Alzheimer disease (AD). Focal deposition beta amyloid adult rat cerebral cortex caused profound neurodegenerative changes, including neuronal loss and degenerating neurons neurites. Chronic induction Alz-50 antigen appeared around focal cortical deposits amyloid. Immunoblot analysis showed that induced Alz-50-immunoreactive proteins were very similar to human from patients with AD. The neuropeptide substance P...
Characterization of soluble oligomeric amyloid β (Aβ) species in the brains Alzheimer's disease (AD) patients and transgenic models has raised possibility that different conformations Aβ may contribute to AD pathology via mechanisms. To characterize toxic effect conformations, we tested side by well characterized oligomers (AβOs), Aβ-derived diffusible ligands (ADDLs), fibrillar (Aβf) preparations human cortical neurons (HCNs). Both AβOs ADDLs bind rapidly with high affinity synaptic...
The cellular mechanisms which lead to the generation and pathological deposition of beta amyloid in Alzheimer's disease are unknown. In this report we describe proteolytic processing precursor protein (APP) an 11.5-kDa COOH-terminal derivative contains full-length sequence. This step normally occurs at low levels parallel with APP maturation secretory pathway. Inhibition oxidative energy metabolism by sodium azide or mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone increased...
Several lines of evidence indicate that alterations in axonal transport play a critical role Alzheimer's disease (AD) neuropathology, but the molecular mechanisms control this process are not understood fully. Recent work indicates presenilin 1 (PS1) interacts with glycogen synthase kinase 3beta (GSK3beta). In vivo, GSK3beta phosphorylates kinesin light chains (KLC) and causes release kinesin-I from membrane-bound organelles (MBOs), leading to reduction driven motility (Morfini et al.,...
Apoptosis plays a role in AIDS pathogenesis the immune system, but its HIV-1-induced neurological disease is unknown. In this study, we examine apoptosis induced by HIV-1 infection of central nervous system (CNS) an vitro model and brain tissue from patients. primary cultures neurons astrocytes as determined terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) propidium iodide staining electron microscopy. was not significantly until 1-2 wk after time peak virus...
Soluble amyloid β oligomers (AβOs) interfere with synaptic function and bind high affinity to synapses, but the mechanism underlying AβO targeting is not known. Here, we show that accumulation of synthetic or native Alzheimer's disease (AD)-brain at synapses regulated by activity. Electrical chemical stimulation increased localization enhanced oligomer formation terminals, whereas inhibition TTX blocked reduced load. The zinc-binding 8-OH-quinoline clioquinol markedly targeting, which was...
The pathological mechanism by which Aβ causes neuronal dysfunction and death remains largely unknown. Deficiencies in fast axonal transport (FAT) were suggested to play a crucial role loss for diverse set of dying back neuropathologies including Alzheimer's disease (AD), but the molecular basis changes FAT undetermined. Recent findings indicate that soluble intracellular oligomeric (oAβ) species may critical AD pathology. Real-time analysis vesicle mobility isolated axoplasms perfused with...
Deposition of fibrillar amyloid β (fAβ) plays a critical role in Alzheimer9s disease (AD). We have shown recently that fAβ-induced dystrophy requires the activation focal adhesion proteins and formation aberrant structures, suggesting mechanism maladaptative plasticity AD. Focal adhesions are actin-based structures provide structural link between extracellular matrix cytoskeleton. To gain additional insight molecular neuronal degeneration AD, here we explored involvement LIM kinase 1...
Bisphenol A (BPA) is a ubiquitous compound that emerging as possible toxicant during embryonic development. BPA has been shown to epigenetically affect the developing nervous system, but molecular mechanisms are not clear. Here we demonstrate exposure in culture led delay perinatal chloride shift caused by significant decrease potassium cotransporter 2 ( Kcc2 ) mRNA expression rat, mouse, and human cortical neurons. Neuronal increased correspondingly. Treatment with epigenetic compounds...
Epidemiological and experimental studies suggest that a disease-aggravating neuroinflammatory process is present at preclinical stages of Alzheimer's disease. Given individuals with Down syndrome are increased genetic risk disease therefore develop the spectrum neuropathology in uniform manner, they constitute an important population to study evolution neuroinflammation across continuum. Therefore, this cross-sectional study, we characterized brain inflammatory profile lifespan syndrome....
Type 2 diabetes (T2D) is a complex metabolic disease associated with obesity, insulin resistance and hypoinsulinemia due to pancreatic β-cell dysfunction. Reduced mitochondrial function thought be central Mitochondrial dysfunction reduced secretion are also observed in β-cells of humans the most common human genetic disorder, Down syndrome (DS, Trisomy 21). To identify regions chromosome 21 that may perturbed glucose homeostasis we profiled glycaemic status different DS mouse models. The...
Abstract The cellular factors regulating the generation of β ‐amyloid from amyloid precursor protein (APR) are unknown. Activation kinase C (PKC) by phorbol ester treatment inhibited 4‐kDa peptide in transfected COS cells, a human glioma cell line, and cortical astrocytes. An analogue diacylglycerol, endogenous activator PKC, also ‐amyloid. PKC increased level secreted APP cells but did not significantly affect primary astrocytes or line. Cell‐associated derivative, ‐amyloid, were...
Background Down's syndrome (DS) is the most common genetic cause of mental retardation. Reduced number and aberrant architecture dendritic spines are features DS neuropathology. However, mechanisms involved in spine alterations not known. In addition to a relevant role synapse formation maintenance, astrocytes can regulate dynamics by releasing soluble factors or physical contact with neurons. We have previously shown impaired mitochondrial function leading metabolic protein processing...
Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of cell bodies. progressively degenerate Alzheimer's disease Down's syndrome, their atrophy contributes to manifestation dementia. Paradoxically, brains, synthesis not affected there abundance precursor, proNGF. We have shown that this phenomenon result deficit NGF's extracellular metabolism compromises proNGF maturation...